1. Field of the Invention
The present invention relates to novel polyquinoline derivatives, to the process for the preparation thereof and to the use thereof as therapeutic agents.
More precisely, compounds according to the present invention are metal ligands and/or dissolve amyloid aggregates and are particularly effective in the treatment of neurodegenerative diseases.
2. Description of the Related Art
Various journals summarise data which demonstrates that many progressive and slow neurodegenerative diseases are associated with: (i) an oxidative stress, (ii) protein misfolding leading to aggregate, fibril, profibril or plaque formation, (iii) an accumulation of these proteins, (iv) synapse loss, (v) homeostasis of the metal ions which have been modified, (vi) axonal and dendritic transport failure, (vii) neural death. (E. Bossy-Wetzel et al., Nature Medecine, 2004, S2-S9; K. J. Barnham et al., Nature Rev. Drug Discov., 2004, 3, 205-214; M. P. Mattson, Nature, 2004, 430, 631-639; P. M. Doraiswamy et al., The Lancet Neurol., 2004, 3, 431-434).
Many studies have recently demonstrated the fundamental role of metal ions (copper, zinc, iron, aluminium, manganese, etc.) in the modification of protein folding and aggregation, leading to serious pathologies. This destructive role of abnormal metal ion-protein interaction has recently been emphasised in many neurodegenerative diseases, (for example: Alzheimer's disease, spongiform encephalopathies, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, etc.) or during the harmful development of some disabilities, as in the case of Down syndrome. A specific protein or specific proteins are associated with each disease, and it has been demonstrated that metal ion chelating agents can be activated to reduce their misfolding brought about by the metals.
In some encephalopathies, such as Creutzfeldt-Jakob's disease and its new variant, it is now acknowledged that these diseases are linked to the transformation of a prion-type protein (PrP) in its pathological and infectious form, known as “scrapie” (PrPsc). Cupric ions are involved in this conformational modification (beta-sheet formation) of the prions, which acquire protease resistance and become insoluble in non-denaturant detergents. Recent works have shown that a ligand such as bathocuproine disulfate can restore in vitro “scrapie” protein PrPsc protease sensitivity and the solubility thereof (E. Quaglio et al., J. Biol. Chem., 2001, 276, 11432-11438).
In the case of Parkinson's disease, the α-synuclein interacts with ferric ions. It has been suggested that these ions facilitate hydroxyl radical formation, in particular oxidising hydroxyl radical formation, and studies using MRI post mortem have shown high concentrations of ferric ions in patients' substancia nigra (a region of the brain where dopaminergic neurones are more selectively affected in this disease). Use of chelators such as Clioquinol reduces the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrapyridine, a toxin which causes Parkinson's disease, in mice (D. Kaur et al., Neuron 2003, 37, 899-909).
In the case of Alzheimer's disease (M. P. Mattson, Nature, 2004, 430, 631-639; M. Citron, Nature Rev. Neurosci., 2004, 5, 677-685), the pathology is linked to aggregation, in the brain, of β-amyloid peptides, leading to amyloid plaque formation. This aggregation may be induced by Cu(II) and Zn(II)ions and, to a lesser extent, by Fe(III) ions. Accumulation within these redox-active metal ion plaques is likely to cause significant oxidative stress (via H2O2 production), itself damaging the neurones in the brain, leading to an irreversible loss of intellectual abilities (M. P. Cuajungco et al., Ann. N.Y. Acad. Sci., 2000, 920, 292-304; C. S. Atwood et al., Met. Ions Biol. Syst., 1999, 36, 309-364). The fact that the first tests to be carried out using a metal ion ligand such as Clioquinol led to improvements in Alzheimer's disease (R. A. Cherny et al., Neuron, 2001, 30, 665-676) indicates that therapeutic approaches using metal ion chelators are possible.
However, these chelators must have the following properties to be able to be used as drugs in the treatment of neurodegenerative diseases:                (a) have a low molecular weight and not be too highly charged in order to be able to cross the various barriers (firstly, intestinal, in the case of a molecule taken orally and then, in a reversible manner, the blood-brain barrier for chelating the metal ions present in excess in the pathogenic proteins),        (b) have a modifiable structure in order to adjust chelation selectivity to specific metal ions (a strong, non-specific chelation would result in a general depletion of metal ions, including those of metalloenzymes, which are essential to the functioning of the organism) or to make it possible to modulate the biodistribution thereof in the organism.        
Chelators with a quinoline unit substituted in position 8 by a heteroatom (such as 8-hydroxyquinoline derivatives, for example) are candidates for chelating the excess metal ions involved in the neurodegenerative diseases. This type of ligand is expected often to form copper, zinc or iron complexes (metal ions associated with protein aggregation and even oxidative stress, with regard to copper and iron), comprising two (and even three in the case of iron) ligands around the metal ion (Sillen, L. G. et al., Stability Constants of Metal-Ion Complexes, The Chemical Society London Publication, 1971).
Bis-quinoline derivatives have been described, but rarely as agents for the treatment of potential diseases of the nervous system. WO 2004/007461 thus describes the property of a metal chelator. However, this document basically describes mono-quinoline compounds. Furthermore, EP 0 443 862 describes NMDA receptor agonist derivatives, and in no way suggests metal chelator activity of the described compounds. Finally, Stockwell et al. in J. Am. Chem. Soc. 1999, 10662-10663 describe the biological activity of the compounds 2,2′-(imino)bis(8-quinolinol) and its derivatives 2,2′-(methylimino)- and 2,2′-(n-butylimino)-bis(8-quinolinol).